David E Leahy Molecular Informatics Group Newcastle University
Development of PBPK Methods <ul><li>Cyprotex  PLC </li></ul><ul><ul><li>HTADMET </li></ul></ul><ul><ul><li>Cloe PK (Generi...
Physiologically Based PK Models <ul><li>Mathematical models of flow and distribution </li></ul><ul><li>Physiological param...
In Vitro ADME <ul><li>Aqueous Solubility </li></ul><ul><li>Cell Membrane Permeability </li></ul><ul><ul><li>Caco-2, MDCK, ...
AUC Predictions by PBPK
Predicted Plasma Levels A, biperiden; B, acecainide; C, dofetilide; D, budesonide
PBPK  versus  Scaling Training Set Caldwell (n=176) I Ward (n=97) PBPK (n=69) Method I Method II Av. Fold E. 2.16 2.22 2.6...
Scaling(Ward Scaling) PBPK Scaling (Caudwell II) Scaling (Cauldwell I)
Summary <ul><li>Generic PBPK models are valid and  at least as good  as inter-specie scaling from rat </li></ul><ul><li>Is...
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PBPK simulation as an alternative to animal testing

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Presentation at Animal Alternatives conference on physiologically based simulation models for reduction of animal testing

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PBPK simulation as an alternative to animal testing

  1. 1. David E Leahy Molecular Informatics Group Newcastle University
  2. 2. Development of PBPK Methods <ul><li>Cyprotex PLC </li></ul><ul><ul><li>HTADMET </li></ul></ul><ul><ul><li>Cloe PK (Generic PBPK) </li></ul></ul><ul><li>Generic PBPK Models for Rat & Humans </li></ul><ul><ul><li>Brightman, Leahy, Thomas & Searle, (Papers I & II) Drug Metabolism and Disposition (2004) </li></ul></ul>
  3. 3. Physiologically Based PK Models <ul><li>Mathematical models of flow and distribution </li></ul><ul><li>Physiological parameters for specie </li></ul><ul><li>ADME Properties for compound </li></ul>
  4. 4. In Vitro ADME <ul><li>Aqueous Solubility </li></ul><ul><li>Cell Membrane Permeability </li></ul><ul><ul><li>Caco-2, MDCK, PAMPA </li></ul></ul><ul><li>Metabolic stability </li></ul><ul><ul><li>Microsomes, hepatocytes </li></ul></ul><ul><li>Distribution </li></ul><ul><ul><li>Lipophilicity (Log D) </li></ul></ul><ul><li>HSA Binding </li></ul>
  5. 5. AUC Predictions by PBPK
  6. 6. Predicted Plasma Levels A, biperiden; B, acecainide; C, dofetilide; D, budesonide
  7. 7. PBPK versus Scaling Training Set Caldwell (n=176) I Ward (n=97) PBPK (n=69) Method I Method II Av. Fold E. 2.16 2.22 2.64 2.48 FE < 2 56% 52% 49% 46% FE < 3 77% 79% 70% 72% FE < 4 88% 86% 79% 75% Test Set Caldwell (n=18) Ward (n=18) PBPK (n=18) Method I Method II Av. Fold E. 2.61 2.53 3.44 2.80 FE < 2 50% 50% 28% 50% FE < 3 56% 56% 44% 61% FE < 4 72% 67% 61% 72% Median P/A 1.74 1.60 2.54 1.11
  8. 8. Scaling(Ward Scaling) PBPK Scaling (Caudwell II) Scaling (Cauldwell I)
  9. 9. Summary <ul><li>Generic PBPK models are valid and at least as good as inter-specie scaling from rat </li></ul><ul><li>Issues </li></ul><ul><ul><li>Different chemistry </li></ul></ul><ul><ul><ul><li>Analytical, model uncertainty </li></ul></ul></ul><ul><ul><li>Different Routes </li></ul></ul><ul><ul><li>Transparency, Provenance, Validation </li></ul></ul>

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